Ubiquitin-Proteasome Pathway (UPP) is a critical pathway that regulates proteins and degrades misfolded or abnormal proteins. UPP is central to multiple cellular processes, and if defective or imbalanced, leads to pathogenesis of a variety of diseases. The covalent attachment of ubiquitin to specific protein substrates is achieved through the action of E3 ubiquitin ligases. These ligases comprise over 500 different proteins and are categorized into multiple classes defined by the structural element of their E3 functional activity. For example, cereblon (CRBN) interacts with damaged DNA binding protein 1 and forms an E3 ubiquitin ligase complex with Cullin 4 in which the proteins recognized by CRBN are ubiquitinated and degraded by proteasomes. Various immunomodulatory drugs (IMiDs), e.g., thalidomide and lenalidomide, binds to CRBN and modulates CRBN's role in the ubiquitination and degradation of protein factors involved in maintaining regular cellular function.
Bifunctional compounds composed of a target protein-binding moiety and an E3 ubiquitin ligase-binding moiety have been shown to induce proteasome-mediated degradation of selected proteins. These drug-like molecules offer the possibility of temporal control over protein expression, and could be useful as biochemical reagents for the treatment of diseases.
Tripartite motif-containing 24 (TRIM24) is a protein kinase transcription regulator of nuclear receptors belonging to the tripartite motif superfamily of proteins. TRIM24 has been shown to interact with numerous proteins involved in chromatin structure and has been implicated as a potential dependency in multiple cancers (including lung and colorectal cancer). TRIM24 has also been shown to induce transformation in breast cancer cell lines. Previously developed ligands for the TRIM24 bromodomain have shown underwhelming biological activity.
Alternative strategies to inhibit transcriptional intermediary factors, such as TRIM24, are needed. At present, suitable compounds with alternative mechanisms of action targeting TRIM24 are not available. The present application addresses the need.